Hepatitis C virus (HCV) infection is a major health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected individuals. Current treatments for HCV infection include immunotherapy with recombinant interferon-α alone or in combination with the nucleoside analog ribavirin.
Several virally-encoded enzymes are putative targets for therapeutic intervention, including a metalloprotease (NS2-3), a serine protease (NS3), a helicase (NS3), and an RNA-dependent RNA polymerase (NS5B). The NS3 protease is located in the N-terminal domain of the NS3 protein. NS4A provides a cofactor for NS3 activity.
Potential treatments for HCV infection have been discussed in different references including Balsano, Mini Rev. Med. Chem. 8(4):307-318, 2008, Rönn et al., Current Topics in Medicinal Chemistry 8: 533-562, 2008, Sheldon et al., Expert Opin. Investig. Drugs 16(8):1171-1181, 2007, and De Francesco et al., Antiviral Research 58:1-16, 2003.
Examples of publications describing macrolactam compounds able to inhibit HCV protease activity include: Holloway et al., U.S. Pat. No. 7,470,664, Harper et al., WO2010011566; Liverton et al., WO2009134624; McCauley et al., WO2009108507; Liverton et al., WO2009010804; Liverton et al., WO2008057209; Liverton et al., WO2008051477; Liverton et al., WO2008051514; Liverton et al., WO2008057208; Crescenzi et al., WO2007148135; Di Francesco et al., WO2007131966; Holloway et al., WO2007015855; Holloway et al., WO2007015787; Holloway et al., WO2007016441; Holloway et al., WO2006119061; Liverton et al., J. Am. Chem. Soc., 130:4607-4609, 2008; McCauley et al., Abstracts of Papers, 235th ACS National Meeting, New Orleans, La., United States, Apr. 6-10, 2008; Liverton et al., Antimicrobial Agents and Chemotherapy 54:305-311, 2009 (published online); and McCauley et al., Journal of Medicinal Chemistry, 53(6):2443-2463, 2010.